Chronic hepatitis B is one of the common chronic infectious diseases in China, which seriously harms people's health. In order to further standardize the prevention, diagnosis and treatment of chronic hepatitis B, the Hepatology Branch of Chinese Medical Association and the Infectious Diseases Branch of Chinese Medical Association, on the basis of referring to the latest research results at home and abroad, organized domestic experts to formulate the Guidelines for the Prevention and Treatment of Chronic Hepatitis B (hereinafter referred to as the Guidelines) according to the principles of evidence-based medicine. Among them, the evidence on which the recommendation is based is divided into three levels and five files [1], which are indicated by italicized Roman numerals in brackets.
This guide only helps doctors to make correct decisions on the diagnosis, treatment and prevention of hepatitis B, and is not a mandatory standard. It is impossible to cover or solve all the problems in the diagnosis and treatment of chronic hepatitis B. Therefore, clinicians should fully understand the best clinical evidence and existing medical resources for a specific patient, and make a reasonable diagnosis and treatment plan based on their own knowledge and experience on the basis of comprehensive consideration of the patient's specific condition and wishes. Due to the rapid progress in the study of chronic hepatitis B, this guide will be constantly updated and improved as needed.
I. Etiology
Hepatitis B virus (HBV) belongs to hepatotropic DNA virus family, and its gene length is about 3.2kb, which is a part of double-stranded circular DNA.
After HBV invades the human body, it combines with the receptor on the liver cell membrane, removes the envelope, penetrates into the cytoplasm of liver cells, and then removes the capsid, and part of the double-stranded circular HBV DNA enters the nucleus of liver cells. Under the action of host enzyme, the negative strand DNA was used as a template to extend the positive strand, repair the crack region in the positive strand, and form closed-loop DNA (cccDNA). Then, under the action of host RNA polymerase II, it is transcribed into several mRNA with different lengths, among which 3.5kb mRNA contains all the genetic information in HBV DNA sequence, which is called pre-genomic RNA. The latter enters the cytoplasm of hepatocytes as a template to synthesize negative-strand DNA under the action of HBV reverse transcriptase. Using negative-strand DNA as a template, positive-strand DNA was synthesized under the action of HBV DNA polymerase to form part of double-stranded circular DNA of offspring, and finally assembled into complete HBV, which was released to the outside of liver cells. Part of the double-stranded circular DNA in cytoplasm can also enter the nucleus of hepatocytes, then form cccDNA and continue to replicate. CccDNA has a long half-life (decay period) and is difficult to be completely eliminated from the body [1, 2].
HBV contains four partially overlapping open reading frames, namely pre-S/S region, pre-C/C region, P region and X region. The pre-S/S region encodes three envelope proteins: large (pre-S- 1, pre-S2 and S), medium (pre-S2 and S) and small (S). Pre-C/C region codes HBeAg and HBcAg；; P region encodes polymerase; The x region encodes the x protein.
Mutations in pre-C region and basic core promoter (BCP) can produce HBeAg-negative mutants. The most common mutation in pre-C region is G 1896A point mutation, which forms a stop codon (TAG) and does not express HBeAg. The most common mutation in BCP region is the joint point mutation of A 1762T/G 1764A, which selectively inhibits the transcription of pre-C mRNA and reduces HBeAg synthesis [3].
The variation of p gene is mainly found in POL/RT gene fragment (349~692 aa, that is, rt 1~rt344). In the treatment of lamivudine, the most common mutation is tyrosine-methionine-aspartic acid-aspartic acid (YMDD), that is, YMDD is mutated into YIDD (rtM204I) or YVDD (rtM204V), which is often accompanied by rtL 180M mutation, and gradually becomes the dominant strain of lamivudine resistance due to drug selection [4] (Ⅰ)
The mutation of S gene can lead to occult HBV infection, which shows that serum HBsAg is negative, but there is still low level of HBV replication (serum HBV DNA is often
At present, HBV can be divided into 8 genotypes (A ~ H) according to the difference of total HBV gene sequence ≥8% or S region gene sequence ≥4%. Each genotype can be divided into different gene subtypes. The response rate of chronic hepatitis B patients with genotype A to interferon therapy is higher than that of genotype D, and genotype B is higher than that of genotype C; Genotypes a and d are higher than genotypes b and C[6](ⅰ). Whether genotype affects the therapeutic effect of nucleoside (acid) analogues has not been determined.
HBV mutates easily. Among HBV-infected people, a virus group with a dominant strain and related mutant strains often forms, and its exact clinical significance needs to be further confirmed.
The resistance of HBV is strong, but HBV can be inactivated at 65℃ 10 h, boiling 10 min or high pressure steam. Chlorine-containing preparations, ethylene oxide, glutaraldehyde, peracetic acid and iodophor also have good inactivation effects.
Second, epidemiology.
HBV infection is widespread all over the world, but the epidemic intensity of HBV infection varies greatly in different regions. According to the statistics of the World Health Organization, about 2 billion people in the world have been infected with HBV, among which 350 million people are chronically infected with HBV, and about 65.438+0 million people die of liver failure, cirrhosis and primary hepatocellular carcinoma (HCC) caused by HBV infection every year [7].
China is a high epidemic area of HBV infection, and the positive rate of HBsAg in general population is 9.09%. The positive rates of HBsAg in people vaccinated with and without hepatitis B vaccine were 4.565438 0% and 9.565438 0% [8] (Ⅲ) respectively. The prevalent HBV serotypes in China are mainly adrq+ and adw2, and a few are ayw3 (mainly found in Xinjiang, Tibet and Inner Mongolia Autonomous Region). Genotypes are mainly C and B [9].
HBV is mainly transmitted through blood and blood products, mother and baby, damaged skin and mucosa and sexual contact [7]. Perinatal (perinatal) transmission is the main mode of mother-to-child transmission, mostly through the blood and body fluids of HBV-positive mothers during childbirth (ⅰ). Transdermal mucosal transmission mainly occurs in the use of medical devices, syringes, invasive diagnosis and treatment operations and operations [1, 10] (II-2), intravenous drug use (I) and so on. Others, such as pedicures, tattoos, earrings, accidental exposure of medical staff at work, use of razors and toothbrushes, can also spread (Ⅲ). Sexual contact with HBV-positive people, especially those with multiple sexual partners, will significantly increase the risk of HBV infection (ⅰ). Due to strict HBsAg screening of blood donors, HBV infection caused by blood transfusion or blood products rarely occurs.
Daily work or life contact, such as working in the office (including using computer and other office supplies), shaking hands, hugging, sharing a dormitory, eating in the same restaurant, using the toilet, etc., generally will not be infected with HBV. Spread by blood-sucking insects (mosquitoes, bedbugs, etc.). ) has not been confirmed.
Third, natural history.
After people are infected with HBV virus, people who are not cleared within 6 months are called chronic HBV infection. Age at the time of infection is the most important factor affecting chronic disease. In perinatal period and infancy, 90% and 25%~30% of HBV infected people will develop chronic infection [11] (Ⅰ). The natural history of HBV infection can generally be divided into three periods, namely, immune tolerance period, immune clearance period and inactive or low (no) replication period [12]. During the immune tolerance period, HBV replication was active, serum HBsAg and HBeAg were positive, HBV DNA titer was high (> 105 copies /ml), serum alanine aminotransferase (ALT) level was normal, and liver histology was normal. In the immune clearance period, the serum HBV DNA titer was >: 105 copy /ml, but it was generally lower than that in the immune tolerance period. The ALT/ aspartate aminotransferase (AST) increased continuously or intermittently, and the liver histology showed necrosis and inflammation. In the inactive period or low (no) replication period, HBeAg is negative, anti -HBe is positive, HBV DNA can not be detected (PCR method) or below the detection limit, ALT/AST level is normal, and there is no obvious inflammation in liver histology.
Only 5%~ 10% of adolescents and adults infected with HBV develop chronic diseases, and generally there is no immune tolerance period. The early stage is immune clearance period, showing active chronic hepatitis B; The late stage can be inactive or low (no) replication stage, and the liver disease is relieved. Whether infected with HBV in perinatal period and infancy, or infected in adolescence and adulthood, some patients can move again and have HBeAg positive conversion in their inactive period or low (no) replication period; Or the promoter of pre-C or C region is mutated, and HBV is active again, but HBeAg is negative, both of which show chronic hepatitis B activity.
In children and adults with HBeAg positive chronic hepatitis B, 50% and 70% [13, 14] developed into inactive or low (no) replication period (II-3, II-2) after 5 years and 10 years, respectively. In China and the Asia-Pacific region, the research on the natural history of chronic HBV infection with no activity or low (non-) replication is not sufficient, but some data show that these patients may have recurrent hepatitis [8]. A prospective study of 684 patients with chronic hepatitis B showed that the estimated annual incidence of cirrhosis in patients with chronic hepatitis B was 2. 1%[ 15]. In addition, 1 HBeAg-negative chronic hepatitis B patients were followed up for an average of 9 years (1~ 18.4 years), and the incidence of progression to cirrhosis and HCC was 23% and 4.4% respectively [16, 17]. High risk factors of liver cirrhosis include high viral load, persistent HBeAg positive, high or fluctuating ALT level, alcoholism, HCV, HDV or HIV infection [18-20] (I). The incidence of cirrhosis in HBeAg positive patients was higher than that in HBeAg negative patients [1, 10,15] (Ⅱ-2).
In patients with chronic hepatitis B, the annual incidence of decompensated cirrhosis is about 3%, and the cumulative incidence in five years is about16% [10] (Ⅰ). The 5-year mortality rates of chronic hepatitis B, compensated cirrhosis and decompensated cirrhosis were 0%~2%, 14%~20% and 70%~86% respectively. The influencing factors included age, serum albumin and bilirubin levels, platelet count and splenomegaly [10] (Ⅱ-2). After spontaneous HBeAg seroconversion or antiviral therapy, the survival rate of patients with persistent negative HBV DNA and normal ALT is higher [10/0,21] (Ⅰ, Ⅱ-3).
HBV infection is an important related factor of HCC, and the incidence of HCC in HBsAg and HBeAg positive patients is significantly higher than that in HBsAg positive patients [22] (Ⅱ-2). The high risk factors of HCC in patients with liver cirrhosis include male, age, alcoholism, aflatoxin, HCV or HDV infection, persistent liver inflammation, persistent HBeAg positive, and persistent high level of HBV DNA (≥105 copies/ml) [10] (i). About 25% people infected before the age of 6 will develop cirrhosis and HCC in adulthood [23] (Ⅱ-2). However, a few HCC patients associated with HBV infection have no evidence of cirrhosis. Family history of HCC is also a related factor, but under the same genetic background, HBV viral load is more important [24] (Ⅱ-3).
Four. prevent
Hepatitis B vaccine prevention
Vaccination with hepatitis B vaccine is the most effective way to prevent HBV infection. 1992 China's Ministry of Health has brought hepatitis B vaccine into the planned immunization management. All newborns are vaccinated with hepatitis B vaccine, but parents have to pay for the vaccine and its vaccination. Since 2002, it has been officially included in the planned immunization, and all newborns are vaccinated with hepatitis B vaccine free of charge, but they have to pay the vaccination fee; Since June 2005 1, it has been changed to free.
Hepatitis B vaccine is mainly aimed at newborns [25], followed by infants and high-risk groups (such as medical staff, people who have frequent contact with blood, staff in nurseries, organ transplant patients, people who often receive blood transfusion or blood products, people with low immune function, people who are vulnerable to trauma, family members of HBsAg positive people, gay men or people who have multiple sexual partners and intravenous drug users, etc.). ). Hepatitis B vaccine was inoculated with ***3 shots in the whole process, according to the procedure of 0, 1 and 6 months, that is, after inoculation with 1 shot, the second and third shots were injected every 1 and 6 months. Newborns should be vaccinated with hepatitis B vaccine as soon as possible, requiring vaccination within 24 hours after birth. Newborns are inoculated into the anterior thigh muscle, and children and adults are injected into the middle muscle of the deltoid muscle of the upper arm. The protective rate of blocking mother-to-child transmission with hepatitis B vaccine alone was 87.8% [26] (Ⅱ-3).
For newborns with HBsAg positive mothers, hepatitis B immunoglobulin (HBIG) should be injected as soon as possible within 24 hours after birth, preferably within 12 hours after birth, and the dose should be ≥ 100 IU. At the same time, 10μg recombinant yeast or 20μg Chinese hamster oocytes (CHO) hepatitis B vaccine should be inoculated in different parts, which can significantly improve the effect of blocking mother-to-child transmission [66 You can also inject 1 dose of HBIG within 12 h after birth, and then inject the second dose of HBIG after 1 month. Inoculate 10μg recombinant yeast or 20μg CHO hepatitis at the same time, and inoculate the second dose and the third dose of hepatitis B vaccine (65438+ each) at intervals of 1 and 6 months respectively. The latter is not as convenient as the former, but its protection rate is higher than the former. After the newborn is injected with HBIG and hepatitis B vaccine within/0/2 h after birth, HBsAg positive mothers can breastfeed [29] (3).
Newborns of HBsAg negative mothers can be inoculated with 5μg recombinant yeast or 10μg CHO hepatitis B vaccine. Children who have not been vaccinated with hepatitis B vaccine in neonatal period should be replanted with 5μg recombinant yeast or 10μg CHO hepatitis B vaccine; It is suggested that adults should be inoculated with 20μg recombinant yeast or 20μg CHO hepatitis B vaccine. For those with low immune function or no response, the vaccination dose and injection times should be increased; Those who do not respond to the three-shot immunization program can be vaccinated with three more shots, and serum anti -HBs can be detected 1~2 months after the second vaccination with three more shots of hepatitis B vaccine.
The protective effect of antibody responders after hepatitis B vaccination can generally last at least 12 years, so the general population does not need anti -HBs monitoring or strengthening immunity. However, anti-HBs monitoring can be carried out for high-risk groups, such as anti-HBS.
(2) Prevention of transmission
Vigorously promote safe injection (including acupuncture needles) and strictly disinfect dental instruments, endoscopes and other medical devices. Medical staff should follow the principle of standard prevention in hospital infection management, and wear gloves when contacting patients' blood, body fluids and secretions to prevent iatrogenic transmission. Haircuts, shaving, pedicures, piercings and tattoos in the service industry should also be strictly disinfected. Pay attention to personal hygiene and don't use razors and dental appliances. Correct sex education, if sexual partners are HBsAg positive, they should be vaccinated with hepatitis B vaccine; People with multiple sexual partners should have regular check-ups, strengthen management and use condoms during sexual intercourse. For HBsAg positive pregnant women, amniocentesis should be avoided, the delivery time should be shortened, the integrity of placenta should be ensured, and the exposure of newborns to maternal blood should be minimized.
(3) Prevention after accidental exposure to HBV
After accidental contact with the blood and body fluids of HBV infected persons, the following measures can be taken:
1. HBsAg, anti -HBs, ALT, etc. should be detected immediately in serological test. , and review within 3 months and 6 months.
2. Active immunization and passive immunization If you have been vaccinated with hepatitis B vaccine, it is known that the anti-HBS is ≥10miu/ml, and no special treatment is needed. If you have not been vaccinated against hepatitis B, or if you have been vaccinated against hepatitis B, but you are anti-HBS.
(4) Management of patients and carriers
Medical staff at all levels should report to the local Center for Disease Control and Prevention (CDC) in a timely manner according to the Law of People's Republic of China (PRC) on the Prevention and Control of Infectious Diseases when they are diagnosed with acute and chronic hepatitis B, and should indicate that it is acute and chronic hepatitis B. It is suggested that serum HBsAg, anti -HBc and anti -HBs should be tested for patients' family members and other close contacts, and the susceptible persons (those with negative three markers) should be vaccinated with hepatitis B vaccine.
For patients with acute and chronic hepatitis B, whether to be hospitalized or treated at home can be decided according to the condition. Medical instruments and appliances used by patients (such as blood collection needles, acupuncture needles, surgical instruments, scraping needles, probes, various endoscopes, dental drills, etc.). ) should be strictly disinfected, especially should strengthen the disinfection of blood-borne pollutants.
Chronic HBV carriers and HBsAg carriers (see "V Clinical Diagnosis" in this guide) can live, study and work as usual except that they cannot donate blood and engage in special occupations (such as military service) stipulated by national laws, but follow-up should be strengthened.
The infectivity of hepatitis B patients and carriers mainly depends on the level of HBV DNA in blood, but has nothing to do with the level of serum ALT, AST or bilirubin. Please refer to "2 1" for the follow-up of hepatitis B patients and carriers. Follow-up of patients. "
Verb (abbreviation of verb) clinical diagnosis
Those who have hepatitis B or HBsAg positive for more than 6 months and HBsAg and/or HBV DNA are still positive can be diagnosed as chronic HBV infection. According to the clinical and auxiliary examination results of HBV infection, such as serology, virology and biochemistry, chronic HBV infection can be divided into:
(1) Chronic hepatitis B
1.HBeAg positive chronic hepatitis B, HBsAg, HBV DNA and HBeAg positive, anti -HBe negative, serum ALT continuously or repeatedly increased, or liver histological examination showed hepatitis lesions.
2. Chronic hepatitis B with negative HBeAg, positive HBsAg and HBV DNA, persistent negative HBeAg, positive or negative anti -HBe, persistent or repeated abnormal serum ALT, or liver histology showing hepatitis lesions.
According to the results of biochemical examination and other clinical and auxiliary examinations, the above two kinds of chronic hepatitis B can be further divided into mild, moderate and severe (see Viral Hepatitis Prevention and Control Program in 2000 [32]).
Hepatitis B cirrhosis
Hepatitis B cirrhosis is the result of the development of chronic hepatitis B, and the histological manifestations of the liver are diffuse fibrosis and false lobulation. Both of them must exist at the same time in order to make a pathological diagnosis of cirrhosis.
1. Compensatory cirrhosis generally belongs to Child-Pugh A grade. There may be mild fatigue, anorexia or abdominal distension, ALT and AST may be abnormal, but there is no obvious decompensation of liver function. There may be portal hypertension, such as hypersplenism and mild esophageal and gastric varices, but there are no esophageal and gastric varices bleeding, ascites and hepatic encephalopathy.
2. Decompensated cirrhosis generally belongs to Child-Pugh B and C grades. Patients often have serious complications such as esophageal variceal bleeding, hepatic encephalopathy and ascites. Most of them have obvious decompensation of liver function, such as serum albumin < 35g/L, bilirubin > 35μ mol/L, ALT and AST increased in different degrees, and prothrombin activity (PTA).
You can also refer to the prevention and treatment scheme of viral hepatitis of 200 1, and divide the compensated and decompensated cirrhosis into active or quiescent phases [32].
(3) the carrier
1. Chronic HBV carriers are positive for HBsAg, HBV DNA, HBeAg or anti -HBe, but they are followed up for more than 3 times in 1 year, and their serum ALT and AST are in the normal range, and there is generally no obvious abnormality in liver histology. Those with positive serum HBV DNA should be mobilized for liver puncture examination for further diagnosis and corresponding treatment.
2. Inactive HBsAg carriers are HBsAg positive, HBeAg negative, anti -HBe positive or negative, HBV DNA can not be detected (PCR method) or below the minimum detection limit, and they are followed up for more than 3 times in 1 year, and ALT is in the normal range. Histological examination of liver showed hepatitis activity index (Hai)
Concealed chronic hepatitis B
Serum HBsAg is negative, but serum and/or liver tissue HBV DNA is positive, which has the clinical manifestations of chronic hepatitis B. Patients may be accompanied by anti -HBs, anti -HBe and/or anti -HBc. In addition, about 20% of patients with occult chronic hepatitis B have negative HBV serological markers except HBV DNA. Liver injury caused by other viral and non-viral factors should be excluded in diagnosis.
Six, laboratory inspection
(1) Biochemical examination
Serum ALT and AST levels were 65438 0. ALT and AST can generally reflect the degree of liver cell injury, and are the most commonly used.
2. Bilirubin Serum bilirubin level is usually related to the degree of hepatocyte necrosis, but it should be differentiated from the increase of bilirubin caused by intrahepatic and extrahepatic cholestasis. The serum bilirubin in patients with liver failure is often high, which increases progressively, increasing by 365,438+0 times of the upper limit of normal value (ULN) every day, which can be ≥ 65,438+00× ULN; Bilirubin can also be separated from ALT and AST.
3. Prothrombin time (PT) and PTA PT are important indexes reflecting the synthesis function of coagulation factors in liver. PTA is a commonly used expression method of PT measurement value, which is of great value in judging the progress and prognosis of diseases. PTA gradually decreased to below 40% recently, which is one of the important diagnostic criteria of liver failure.
4. Cholinesterase can reflect the synthetic function of the liver, which is of reference value for understanding the severity of the disease and monitoring the development of liver disease.
5. Serum albumin reflects the synthetic function of liver. The decrease of serum albumin or the increase of globulin in patients with chronic hepatitis B, liver cirrhosis and liver failure indicate that the ratio of serum albumin to globulin is decreased.
6. The obvious increase of alpha-fetoprotein (AFP) often indicates HCC, which can be used to monitor the occurrence of HCC. The increase of AFP can also indicate the regeneration of hepatocytes after massive necrosis, which may be helpful to judge the prognosis. However, we should pay attention to the amplitude, duration and dynamic changes of AFP and its relationship with ALT and AST, and make a comprehensive analysis based on the clinical manifestations of patients and the results of imaging examinations such as B-ultrasound.
(b) serological detection of B)HBV.
The serological markers of HBV are HBsAg, anti -HBs, HBeAg, anti -HBe, anti -HBc and anti -HBc Ig M. At present, the commonly used detection methods are enzyme immunoassay (EIA), radioimmunoassay (RIA), microparticle enzyme immunoassay (MEIA) or chemiluminescence method. HBsAg positive indicates HBV infection; Anti -HBs is a protective antibody, and its positive indicates that it is immune to HBV. This antibody exists in patients with hepatitis B rehabilitation and hepatitis B vaccination. HBsAg turns negative and anti -HBs turns positive, which is called HBsAg serological conversion; HBeAg positive can be used as an indicator of HBV replication and high infectivity. Anti-HBe positive indicates that HBV replication level is low (except for pre-C mutation); HBeAg turns negative and anti-HBe turns positive, which is called HBeAg seroconversion; Positive anti-HBc IgM indicates HBV replication, which is more common in the acute phase of hepatitis B. The total anti-HBc antibody is mainly anti-HBc IgG. As long as HBV is infected, this antibody is positive whether the virus is eliminated or not.
In order to know whether HBV and hepatitis D virus (HDV) are co-infected or overlapped, HDAg, anti-HDV, anti-HDV IgM and HDV RNA can be determined.
(3) Detection of 3)HBV DNA, genotype and variation.
The qualitative and quantitative detection of 1.HBV DNA reflects the situation or level of virus replication, and is mainly used for the diagnosis of chronic HBV infection, the monitoring of serum HBV DNA and its level, and the evaluation of antiviral efficacy.
2.2 common methods. HBV genotyping includes (1) genotype-specific primer PCR(2) restriction fragment length polymorphism analysis (RFLP); (3)inno-lipa； (4) PCR microplate nucleic acid hybridization enzyme-linked immunosorbent assay; (5) gene sequencing, etc. However, there is no HBV genotyping kit officially approved by SFDA in China.
3. The commonly used methods for detecting HBV-resistant mutants [33, 34] include: (1) gene sequence analysis of HBV polymerase region; (2) Restriction fragment length polymorphism analysis (RFLP); (3) Fluorescence real-time PCR(4) Linear probe reverse hybridization.
Seven. Imaging diagnosis
The liver, gallbladder and spleen can be examined by B-ultrasound, computed tomography (CT) and magnetic resonance imaging (MRI). The main purpose of imaging examination is to identify, diagnose and monitor the progress of chronic hepatitis B, and to find space-occupying lesions of the liver, such as HCC.
Eight, pathological diagnosis
The liver histopathological features of chronic hepatitis B are as follows: obvious portal vein inflammation, the infiltrated inflammatory cells are mainly lymphocytes, and a few are plasma cells and macrophages; Aggregation of inflammatory cells often leads to the expansion of portal area, and can destroy the boundary plate and cause interfacial hepatitis, also known as flaky necrosis. Inflammation in portal area and its interfacial hepatitis are the characteristic pathological changes of chronic hepatitis B. The degeneration and necrosis of hepatocytes in lobules, including fusion necrosis and pontine necrosis, become more and more obvious with the aggravation of the disease. Inflammatory necrosis of liver cells, portal area and interface hepatitis can lead to excessive deposition of liver collagen, liver fibrosis and fibrous septa formation. If it is further aggravated, it can cause structural disorder of hepatic lobule, form false lobule and progress to cirrhosis.
Immunohistochemical detection can show whether hepatitis B surface antigen and hepatitis B surface antigen are expressed in hepatocytes. The expression of HBsAg cytoplasmic diffuse type and membrane type, HBcAg cytoplasmic type and membrane type suggests that HBV replication is active; The expression of HBsAg inclusion type, peripheral type and HBcAg karyotype suggests the existence of HBV in hepatocytes.
Please refer to 200 1 [32] for the classification (g) of inflammation and necrosis of liver tissue and the staging (s) of fibrosis degree of chronic hepatitis B. At present, Knodell HAI scoring system is widely used in the world, and Ishak, Scheuer and Chevallier scoring system or semi-quantitative scoring scheme can also be used to understand the degree of liver inflammation, necrosis and fibrosis, and evaluate the efficacy of drugs [35-38].
Nine, the overall goal of treatment
The overall goal of the treatment of chronic hepatitis B is to inhibit or eliminate HBV for a long time, reduce the inflammatory necrosis and hepatic fibrosis of hepatocytes, delay and prevent the progress of the disease, and reduce and prevent the occurrence of liver decompensation, cirrhosis, HCC and its complications, thus improving the quality of life and prolonging the survival time.
The treatment of chronic hepatitis B mainly includes antivirus, immunomodulation, anti-inflammation, liver protection, anti-fibrosis and symptomatic treatment, among which antiviral treatment is the key. As long as indications and conditions permit, standardized antiviral treatment should be carried out.
X. general indications for antiviral therapy
General indications include: (1) HBV DNA≥ 105 copy /m l (HBeAg negative ≥ 104 copy/ml); (2)ALT≥2×ULN； If treated with interferon, ALT should be ≤ 10×ULN, and the total bilirubin level should be
(1) and (2) or (3) patients should be treated with antiviral therapy; For those who can't meet the above treatment standards, we should monitor the changes of the disease, such as persistent HBV DNA positive and abnormal ALT, and also consider antiviral treatment (III).
Attention should be paid to exclude the increase of ALT caused by drugs, alcohol and other factors, and also to exclude the temporary normal ALT after the application of enzyme-lowering drugs. In some special cases, such as liver cirrhosis, the level of AST can be higher than that of ALT, and the level of AST can be referred to for such patients.
XI。 Response to antiviral therapy
Treatment response contains many contents and there are many classification methods.
(1) single response
1. Virological response means that serum HBV DNA is not detected (PCR method) or below the detection limit, or ≥2 log 10 lower than the baseline.
2. Serological reaction refers to the seroconversion from HBeAg to negative or HBsAg to negative.
3. Biochemical reaction means that serum ALT and AST return to normal.
4. Histological reaction refers to the improvement of liver histological inflammation, necrosis or fibrosis to a specified value.
(2) Time series response
1. initial or early reaction (initial or early reaction) treatment 12 weeks later.
2. Reaction after treatment.
3. Follow-up for 6 months or more 12 months after continuous response therapy, the curative effect is unchanged and there is no recurrence.
4. During the antiviral treatment, the maintenance reaction showed that HBV DNA could not be detected (PCR method) or was below the detection limit, or ALT was normal.
5. The breakthrough reached the initial reaction, but without changing the treatment, the DNA level of HBV increased again, or once turned negative and then turned positive again, with or without ALT increase. Sometimes it also means that after the normalization of ALT and AST, they will increase again without changing the treatment, but the increase of ALT and AST caused by other factors should be excluded.
6. At the end of the treatment, the recurrence is relieved, but HBV DNA rises again or turns positive after stopping the drug, sometimes it means that ALT and AST rise again after stopping the drug, but the rise of ALT and AST caused by other factors should be excluded.
(3) Joint reaction
1. Complete response, Cr) After treatment, ALT returned to normal, HBV DNA could not be detected (PCR method) and HBeAg serum turned negative; In chronic hepatitis B patients with negative HBeAg, ALT returned to normal after treatment, and HBV DNA could not be detected (PCR method).
2. Partial reaction (PR) is between complete reaction and no reaction. For example, in patients with HBeAg-positive chronic hepatitis B, ALT and HBV DNA returned to normal after treatment.
3. No response, NR) Not up to the above respondents.
Twelve, interferon therapy
Meta-analysis showed that after 4~6 months of treatment with interferon A, the negative rates of HBV DNA (hybridization method) in the treatment group were 37% and 17%, respectively, while those in the untreated group were 12%, and the negative rates of HBeAg and HBsAg were 7.8% and 65438+, respectively. The randomized controlled trial of four HBeAg negative patients showed that the effective rate was 38%~90% at the end of treatment, but the continuous effective rate was only 10%~47% (average 24%) [40,41] (Ⅰ). According to reports, the course of treatment of common IFNa is at least 65,438+0 years to obtain better curative effect [42-44] (Ⅱ). Ordinary IFN a (5MU subcutaneous injection, one day 1 time) is used to treat patients with chronic hepatitis B. Some patients may have elevated ALT, and a few even have jaundice. When treating patients with compensated hepatitis B cirrhosis, the incidence of liver function decompensation is
The international multicenter randomized controlled clinical trial showed that HBeAg-positive chronic hepatitis B (87% Asians) was treated with pegylated interferon A-2A (40 KD) for 48 weeks and followed up for 24 weeks. The seroconversion rate of HBeAg was 32% [46,47]. HBeAg negative patients (60% Asians) were followed up for 24 weeks after 48 weeks of treatment, HBV DNA
For patients with recurrence after treatment with common IFNα, the curative effect can still be obtained after treatment with common IFNα [42 42,50] (II), and other common IFN A subtypes, PegIFNa-2a or nucleoside (acid) analogues can also be used for treatment.